Piperidine derivative and process of producing the same



Patented M11 21, 19 29.

UNITED STATES TEN OFFICE.

SAMUEL M. MCELVAIN, OF MADISON, WISCONSIN.-

rnmammn DERIVATIVE mp raocnssor raonucme rim sum.

- No Drawing.

, In the above formula, R and R represent various alkyl groups, and R represents an aromatic grouping. An example of a sub 20- stance having the formula given above, 1s.

A 1-alkyl-3-carbalkoxy-4-piperidyl benzoate.

Compounds of the character designated in the above formula may beprepared in the following manner. A primary alkyl amine, such as isoamyl is caused to react with alkyl ,8 halogen propionate, preferably ethyl-,8- bromopropionate, in alcoholic solution. This reaction may be carried out with'or without a condensing agent, such as silver oxide, to give the tertiary amine, B, ,8 dicarbalkoxy diethyl alkyl amine. The reaction stated may be carried out without artificial heating. The tertiary amine thus produced ,is separated from the mixture, as by, dis tilling oil the alcohol. V The tertiary amine is then purified by fractional distillation. The purified tertiary amine is then condensed, either alone or in the presence ofa non-reacting diluting solvent, such as benzene, toluene, xylene, 0r cymene, by means of a condensing agent, such as an alkali metal, an alkali metal alkoxide, or an alkali metal amide. The con densing may be effected by heating, fo'r'example, at 100-150 C. for thirty minutes.v Thus, one obtains, in the illustration given,

a compound which may be designated l-alkyl- 3-carbalkoxyi piperidone.

such as sodium amalgam, or a catalytic reduc- 5 0 tion agent, such as platinum, the'corresponding 4-hydroxy piperidines. The reduction may be accomplished without heating by sodium amalgam in aqueous solution; or by shaking with hydrogen under pressure "and platinum as a catalyst a solution of the piper- 1done in water or alcohol,

Application filed June a,

roduced by thevv The piperidonen yields, on reduction with a-suitable .agent,.

1926. Serial No. 113,558.

The hydroxypiperidine thus produced is then acylated, for example, by a treatment with benzoyl chloride or benzoic anhydride, or substituted derivatives thereof, to correspondto the compound designated b the formulagiven above. Where the acylation is accomplished by benzoylating the piperidine Wltll benzoyl chloride, for example, the reignatetl 1-alkyl-3-carbalkoxy 4 piperidyl benzoate.

Such a base may be converted to a salt by treatment witha suitable acid, such as lactic,-

tartaric, phosphoric, sulphuric, hydrochloric, etc. Such a salt is soluble in water and suitable for use as a local anaesthetic. The lac tat-e maybe represented by the formula:

GH: CHCOOR orncnorrcoon. RN cnoooot'rn CHg-CH2 h and the hydrochloride may be represented as CH:CHC0OR' CHr-CH: v

I have discovered and produced a series of compounds having the general formulastated above which may be readily converted into the corresponding salts by treatment with acid; and some of these salts have been demonstratedto possess very strong anesthetic properties and to be, at the same time, of markedly low toxicity. It is possible to produce, for example, local anesthetics by the improved process having many times the anesthetic power of cocaine. Again, it is possible to produce by the improved process a local anesthetic of considerably greater anesthetic power than cocaine and having decidedly less'toxicity.

, The following examples will serve to illustrate the process and the products, orcompounds, which may be produced in accordance with the present invention:

Example I.1isomnyZ-i-carbetkowyi-piperidylbenzoate. i

A solution of 32 g. of isoamyl amine in 400 cc. of 95% alcohol is treated with ethyl fi-bromopropionate and the solution stirred until theheat of the reaction subsides. Then, with stirrin continued, g. of silver oxide is added fol owed by 35 g.- more of the ethyl i- ,B-bromopropion'ate. After the heat caused. by this addition hasisubsided, 40 g.

sultant product is a base which may be desg. of

moreofsilver'oxideis added Thisisfollowed' stirred for one hour.

by another 35 g. portion of the propionate and 40 g. portion of the oxide. The mixture 1s After this the silver halide is filtered off and the alcohol is dis- 'tilled'ofi" of the filtrate. The remaining oil is distilled and the fraction boiling at ISO-190 at2 mm. of mercury is collected as B, B dicarbethoxy diethyl isoamyl amine. Temperatures stated herein are eentigrade.

A solution of 42 g. of this tertiary amine in 50 cc. of xylene is treated with 3.5 g. of pow dered sodium in anoil bath at the refluxing temperature of the xylene for thirty minutes. The reaction mixture is cooled and extracted. with water. The aqueous layer is chilled and acidified to Congo red with hydrdchloric acid.

The acidsolution is then made alkaline with potassium carbonate and the piperidone exhol-ether mixture is awhite crystalline prodtracted with ether. The piperidone is then precipitated from the ether as the hydrochloride. This salt recrystallized from an alco not which melts at 155.

A solution oflO g. of the'piperidone hydrochloride in absolute alcohol is shaken with hydrogen under pressure in presence of a suit: able catalyst, such as platinum, until a test portion of the solutionsho'ws no red coloration with ferric chloride solution. .:The cata lyst is then filtered from the solution, and the solution evaporated to dryness in, yaeuo;

. Twenty cc. of benzoyl chloride is added to the residue from the evaporation and. the mixture is heated in an oil bath at' 160-180" until the.

evolution of H01 ceases. The resulting're'ac .tion mixture isjdiluted with ether andthe' precipitated l-isoamyl-3 carhethoxy-4-piper" idyl benzoate hydrochloride is recrystallized e5 manner as-the isoamyl derivative except that i from an alcohol-ether mixture. product which melts at 181.

' It is a white I The-foregoing reactions ma; be graphically.

l isoaniyl-3-carbethbiyA-piperidcne i-mm l-s-mupgwei maiium Emdmplc Il.'-1 n cow Z93 cerhetzwlmy 4 V pipqfldyl benzoate.

This' compound is prepared in the same procedure as I E'qrample V:-

pears asa white product m'eltingat 2159..

Ezpample VI .1 iso butyl 3 carbethomy 7 1,-

Example III- n-bdtg Z 3 carbetltoazy 4- piperidylbencoate. Y t

This compoundis prepared by the above procedure "using 27 g. of'n-butyl amineinstead of the amyl amine. The tertiary amine fraction boils at=140-160. The piperidone drochloride melts 1111177.".

fi p dyl benzoate.

-This compound is prepared by the same the n-butyl compound. .The'

tertiary amine fraction boils at 140 1805;

hydrochloride melts at 129, and the 1-n butyl-3-carbethoxy 4-piperidy1 benaoatehy- The piperidone hydrochloride melts at'.126-.

zoate hydrochloridelnelts at 199.

:The 1-isobutyl 3-carbetl1oxy-4-piperidy] ben- The residue, describedin'Example I, re-' sulting from-the evaporation ih vacuo of the solution er the reduction product of 1-isoamyl 3-carbethoxyA-piperidone' hydrochloride istreated with 20 g. of vp-nitrobenzoyl chloride and the mixture is heated in 'anioil' bath at 140-160 until the evolut ceases. The reaction mixture luted with ether and the .precip chloride of the p-nitro benzo" ion of H01 cooled, di-' s 'recry'stallized. from. an alcohol-eth mixture.- It

' melts at 169% I A solution of 10 g. ofthis salt in alcohol is shaken with hydrogen'under pressure in the presence of a suitable catalyst, such as platinum, until the necessary amount of hydrogen" forthe reduction is absorbed. The catalyst is After crystallization from alcohol-ether mix ture, the dihydrochloride-of I-isoamyl-3-carhethoxy--lpiperidyl-p-amino. benzoate apyipezidyl pamino benzoate.

This compound ispre ared in the manner which has been describe for the isoamyl derivative in Example V, using the corresponding isobutyl derivatives instead of the iso The hydrochloride ofv-the amyl' derivative. p -nitro benzoate melts at 206?. The dihydrofilteredlfrom the solution and the solution evaporated to dryness invacuo. The base may be isolated as the dihydrochlorider.

Example lV.-1 ieobutgqlfi-carbethozc dhydro- E? v chloride of 1 isobdtyl-E carbethoXyA-piperidyl-P-amino benzoate melts at- 232.

Example vV'Il.1 n-butyZ-warbairway-.4- 'piperz'dyl-p -amino benzoate.

This substance is prepared by the procedure given in Example V, using the corresponding n-butyl derivative instead of the isoamyl derivative. The hydrochloride of the p-nitro benzoate melts at 194. The dihydrochloride of 1-nbutyl-3-carbethoxy-4-piperidyl-p-animo benzoate melts at 230.

Examples of rimary alkyl amines which may be used in the process are methyl,-ethyl, n-propyl, isopropyl, secondary butyl, isoamyl, n-amyl, and other of the higher alkyl amines. The amyl amines appear to be particularly good in the process, and especially isoamyl.

Examples of alkyl B halogen propionates which may be employed are methyl, ethyl,

and n-propyl. The use of ethyl B-bromopropionate is preferred.

Examplesof condensing agents for converting the tertiary amines to piperidones are the alkali metals, alkali metal alkoxides,

and alkali metal-amides, such as sodium, sodium ethoxide, etc.

Examples. of reducing agents fo'r reducing the piperidones to hydroxy piperidines'are sodium amalgam in aqueous solution, and

hydrogen under pressure, with platinum, palladium, or nickel, as a catalyst, the piperidones being preferably in alcoholic solution.

--Examples of acylating agents suitable for converting the hydroxy piperidine's to the piperidyl benzoates, for example, are benzoyl chloride, methyl benzoyl chlorides, benzoic anhydride, methyl benzoic anhydrides, ni-

tro-benzoyl chlorides, etc, In the case of nitro-benzoyl chloride, the. acylat-ing, action is followed by the useof a reducing agent, such as iron or tin, in acid solution, or by catalytic reduction with hydrogen under. pressure in the presence of a catalyst, such as platinum, palladium, or nickel. The reduction product obtained by either of the last-mentioned methods may be converted into a salt by treatment with acid, or it may be first alkylated to substitute either one or 'two 'alkyl groups, and then converted into a salt by treatment with acid. Alkylatedproducts of .the following general formulae can thus be produced F on, 030003 RN cH'ooommNHR" where R,R, R", and R are alkyl radicals.

Among the acids which may be used for formingthe salts may be mentioned lactic,

,the type herein described and tartaric, phosphoric, sulfuric, hydrochloric and other acids.

In some cases,\;,the,use of organic acids is particularly desirable as tending to produce a salt which will be non-irritating becausemore nearly neutral. It ma he -mentioned,

however, that in .the case of t e amino benzoates, good results are obtained by the use of mineral acids,- such as hydrochloric or sulfuric, to produce the salts. The examples given above are illustrative or discovery. In the appended claims, theexpression phenyl group is used to designate both the non-substituted phenyl group and the substituted phenyl groups.

It is to be understood that I intend to be protected broadly for novel com ounds of,

thereof including bases, salts or substitution products thereof.

erivatives of the process and products of my invention,

The foregoing detailed description hasbeen 'given for'clearness of understanding only, and no unnecessary limitations shouldbe understood therefrom, but the appended claims should be construed as broadly as permissible, in view of the prior art.

What'I regard as new, and desire to secure by Letters Patent, is:

1. A pi eridinederivative whose formula includes t e grouping omoHoooR' RN, HOCOR Hz in which R and R' are alkyl groups and R is an aromatic grouping. 2. A piperidine derivative whose formula includes the grouping omcnooon' RN HQCQR in which R and R are alkyl groupsand R comprises a phenyl group. v

3. A composition as expressed in claim 2,

in which R comprises a substituted phenyl Q which R is an alkylgroup having not more than three carbon atoms. 8. The composition stated in claim 2,-1n which R is an ethyl group.

than three carbon atoms.

9. The composition stated in claim 1,2 which is an alkyl group v g ot more a p 10. The composition stated inclaim 2, in I .which R is an alkyl group containing more than three carbon atoms.

11, A composition as stated in claim 2, in which R is an alkyl group containing more than three and less than sixcarbon atoms.

12. A composition as stated in'claim 2, in

' which R is an amyl radical.

which R is an alkyl group having not more than three carbon atoms and R is a substiituted phenyl group. I

17. The salt of an acid and a base in accordance with the formula stated in claim 1.

18. The salt of .an acid and a base /in accordance with the formula stated in claim 2.

5 19. The-salt of an acid and a base in acl cordance with the formula stated in claim 2 in which R is a substitutedphenyl group.

ance with the R is an amino-substituted phenyl group.

. ing a 4 20. The salt of an acid and a base in accordance with the formula stated in cairn 2 in which R is an amyl radical.

21. The salt of a mineral acid and a base in accordance with theformula set forth in claim 2 in which R is an amino-substituted phenyl group.- i

22. The hydrochloride of a base in accord- .formula of claim 2 in which 23. The process which comprises: caus-,

reaction between a primary,-alky1 amine and alkyl ,B-halogen propionate, separating the ,6, amine ,thus produced and condensing it by heating with a condensing agent adapted to eliminate a molecule of alcohol, thus-forming 1-alkyl-3-carbalkoXy-4-piperidone, treating the last-mentioned product with a reducing agent and thereby converting the ketone group thereof into an alcohol group, acylating with an agent containing a nitro-substi- ,tuted' phenyl group, reducing the nitrogroup' and alkylating the resultant primary amino group.

S MUEL M. McELVAIN.

B dicarbalkoxy diethyl alkyl 

